Urinary Adenosine and Aminoimidazolecarboxamide Excretion in Methotrexate-Treated Patients With Psoriasis

Baggott, Joseph E.; Morgan, Sarah; Sams, W. Mitchell; Linden, Joel

doi:10.1001/archderm.135.7.813

Cited by 46 publications

(42 citation statements)

References 27 publications

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“…More relevant to its anti-inflammatory action, patients taking low-dose methotrexate for psoriasis also excrete increased aminoimidazole carboxamide in their urine, further confirming the hypothesis that methotrexate promotes AICAR accumulation (Baggott et al, 1999). AICAR accumulation causing adenosine release was first suggested by Gruber and colleagues (Gruber et al, 1989) who showed that intracellular AICAR accumulation (induced by infusion of AICARiboside) is associated with increased adenosine release in vivo.…”

Section: Methotrexate Increases Extracellular Adenosine Concentratmentioning

confidence: 65%

“…In those patients with central nervous system toxicity, administration of an adenosine receptor antagonist rapidly reversed the toxicity, indicating that the adenosine released into the central nervous system is sufficient to occupy adenosine receptors and dramatically alter central nervous system function. Two studies in patients provide evidence that methotrexate increases adenosine release (Laghi Pasini et al, 1997;Baggott et al, 1999).…”

Section: Methotrexate Increases Extracellular Adenosine Concentratmentioning

confidence: 99%

See 1 more Smart Citation

Low-Dose Methotrexate: A Mainstay in the Treatment of Rheumatoid Arthritis

Cronstein¹

2005

Pharmacol Rev

462

311

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Section: Methotrexate Increases Extracellular Adenosine Concentratmentioning

confidence: 65%

Section: Methotrexate Increases Extracellular Adenosine Concentratmentioning

confidence: 99%

Low-Dose Methotrexate: A Mainstay in the Treatment of Rheumatoid Arthritis

Cronstein¹

2005

Pharmacol Rev

462

311

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“…More important, oral lowdose methotrexate treatment leads to a marked increase in adenosine release from whole blood of patients and a significant increase of adenosine excretion into their urine (26,27). In contrast to the results reported in animals and in humans with rheumatoid arthritis and psoriasis, observations by Egan and coworkers (28) do not support the effect of methotrexate on adenosine release from inflamed bowel.…”

Section: Discussionmentioning

confidence: 99%

Adenosine A_2A or A₃ receptors are required for inhibition of inflammation by methotrexate and its analog MX‐68

Montesinos¹,

Desai²,

Delano³

et al. 2003

Arthritis & Rheumatism

189

116

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Objective. Low-dose weekly methotrexate therapy remains a mainstay in the treatment of inflammatory arthritis. Results of previous studies demonstrated that adenosine, acting at one or more of its receptors, mediates the antiinflammatory effects of methotrexate in animal models of both acute and chronic inflammation. We therefore sought to establish which receptor ( Results. Low-dose weekly methotrexate treatment increased the adenosine concentration in the exudates of all mice studied and reduced leukocyte and tumor necrosis factor ␣ accumulation in the exudates of wildtype mice, but not in those of A 2A or A 3 receptor knockout mice. Dexamethasone, an agent that suppresses inflammation by a different mechanism, was equally effective at suppressing leukocyte accumulation in A 2A knockout, A 3 knockout, and wild-type mice, indicating that the lack of response was specific for methotrexate and MX-68.Conclusion. These findings confirm that adenosine, acting at A 2A and A 3 receptors, is a potent regulator of inflammation. Moreover, these results provide strong evidence that adenosine, acting at either or both of these receptors, mediates the antiinflammatory effects of methotrexate and its analog MX-68.Low-dose weekly methotrexate is the "gold standard" of therapy in rheumatoid arthritis and other inflammatory diseases. Methotrexate's mechanism of action in the treatment of inflammatory diseases has been the subject of some controversy, although in previous studies, investigators in our group have demonstrated that adenosine mediates the antiinflammatory effects of methotrexate treatment in models of acute and chronic inflammation (1,2). Adenosine, whether released from injured cells or tissues or applied exogenously, regulates inflammation via interaction with one or more of the 4 known receptors for adenosine (A 1 , A 2A , A 2B , and A 3 ), as demonstrated by many in vitro and in vivo pharmacologic studies (for review, see ref.3). The demonstration that adenosine mediates the antiinflammatory effects of methotrexate in in vivo models of acute inflammation rests upon reversal of the antiinflammatory effects of methotrexate, either by enzymatic hydrolysis of adenosine by adenosine deaminase or by administration of adenosine receptor antagonists to reverse the antiinflammatory effects of methotrexate treatment (1,2). Although the antiinflammatory effects of methotrexate are mediated by multiple adenosine receptors in the adjuvant arthritis model of inflammation (2), the identity of the receptor(s) involved in the suppression of inflammation in models of acute inflammation has not been so well characterized.

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“…These remarkably constant values under normal conditions could provide a basis for the evaluation of renal adenosine excretion as a marker of renal injury in various clinical settings. In fact, enhanced renal adenosine excretion rates were found during renal ischemia (215), maleic acid (10), radiocontrast media application (154), and methotrexate (12).…”

Section: Renal Excretion Of Adenosinementioning

confidence: 99%

Adenosine and Kidney Function

Vallon

Mühlbauer²,

Oßwald³

2006

Physiological Reviews

396

379

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In this review we outline the unique effects of the autacoid adenosine in the kidney. Adenosine is present in the cytosol of renal cells and in the extracellular space of normoxic kidneys. Extracellular adenosine can derive from cellular adenosine release or extracellular breakdown of ATP, AMP, or cAMP. It is generated at enhanced rates when tubular NaCl reabsorption and thus transport work increase or when hypoxia is induced. Extracellular adenosine acts on adenosine receptor subtypes in the cell membranes to affect vascular and tubular functions. Adenosine lowers glomerular filtration rate (GFR) by constricting afferent arterioles, especially in superficial nephrons, and acts as a mediator of the tubuloglomerular feedback, i.e., a mechanism that coordinates GFR and tubular transport. In contrast, it leads to vasodilation in deep cortex and medulla. Moreover, adenosine tonically inhibits the renal release of renin and stimulates NaCl transport in the cortical proximal tubule but inhibits it in medullary segments including the medullary thick ascending limb. These differential effects of adenosine are subsequently analyzed in a more integrative way in the context of intrarenal metabolic regulation of kidney function, and potential pathophysiological consequences are outlined.

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Urinary Adenosine and Aminoimidazolecarboxamide Excretion in Methotrexate-Treated Patients With Psoriasis

Cited by 46 publications

References 27 publications

Low-Dose Methotrexate: A Mainstay in the Treatment of Rheumatoid Arthritis

Low-Dose Methotrexate: A Mainstay in the Treatment of Rheumatoid Arthritis

Adenosine A_2A or A₃ receptors are required for inhibition of inflammation by methotrexate and its analog MX‐68

Adenosine and Kidney Function

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Urinary Adenosine and Aminoimidazolecarboxamide Excretion in Methotrexate-Treated Patients With Psoriasis

Cited by 46 publications

References 27 publications

Low-Dose Methotrexate: A Mainstay in the Treatment of Rheumatoid Arthritis

Low-Dose Methotrexate: A Mainstay in the Treatment of Rheumatoid Arthritis

Adenosine A2A or A3 receptors are required for inhibition of inflammation by methotrexate and its analog MX‐68

Adenosine and Kidney Function

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Adenosine A_2A or A₃ receptors are required for inhibition of inflammation by methotrexate and its analog MX‐68